tbuckley/cabot-search huggingface dataset:
Reply to Z.R. McCaw et al
Authors: Jason E. Farrar, Megan Othus, Yi-Cheng Wang, Todd A. Alonzo, Soheil Meshinchi
Journal: Journal of Clinical Oncology (2023)

We agree that further research is needed for identification of better biomarkers for initial therapy selection in pediatric AML and thank the authors for an additional opportunity to emphasize this important point. 1 Indeed, the concordance statistic alluded to in this letter and presented in Data Supplement (Table S9) 2 of 0.659 for overall survival in the cytogenetic-fusion-molecular stratification scheme represents the state of the art in current clinical use in North American/Children's Oncology Group studies (with the caveats of application to a retrospective cohort); clearly, there is ample room, and need, for improvement.We hope that this manuscript, others' work in adult AML long non-coding RNA (lncRNA) expression, the companion lncRNA primer 3 accompanying the primary research paper, and this commentary thread will further spur work in refinement and application of lncRNA biomarkers for risk estimation and therapy selection.We also wholeheartedly agree that P values should not be the sole criterion by which novel biomarkers are judged for suitability to direct therapy; we hope that the readership will consider the full range of statistical, clinical, and pragmatic arguments outlined in the manuscript in evaluating our claim for the potential benefit of the lncScore in pediatric AML risk stratification. 1
Reply to D. Wu et al
Authors: Roy S. Herbst, Yi-Long Wu, Masahiro Tsuboi
Journal: Journal of Clinical Oncology (2023)

We thank Wu et al 1 for their comments on our manuscript reporting the final disease-free survival (DFS) analysis from the ADAURA phase III trial. 2 We reported all treatmentemergent adverse events that occurred during osimertinib and placebo treatment in the noted safety tables.For this final DFS analysis, we considered that reporting all-causality adverse events was the most transparent way to present the data.Decisions about causality of an adverse event are complex and subjective and may differ depending on who assesses potential causality. 3 We recognized the importance of reporting safety data, and for this reason, a comprehensive analysis of ADAURA safety data has been presented recently by John et al 4 at the European Society for Medical Oncology Asia 2022 meeting, including an in-depth analysis of adverse events of special interest, such as interstitial lung disease, cardiac effects, and QTc prolongation.
A Randomized, <scp>Double‐Blind</scp>, <scp>Sham‐Controlled</scp>, Clinical Trial of Auricular Vagus Nerve Stimulation for the Treatment of Active Rheumatoid Arthritis
Authors: Matthew C. Baker, Sarah Kavanagh, Stanley Cohen, Alan K. Matsumoto, Ara Dikranian, John Tesser, Alan Kivitz, Konstantinos Alataris, Mark C. Genovese
Journal: Arthritis & Rheumatology (2023)

Preliminary evidence suggests that vagus nerve stimulation (VNS) may have some benefit in patients with rheumatoid arthritis (RA); however, prior studies have been small and/or uncontrolled; this study aimed to address that gap.This randomized, double-blind, sham-controlled trial enrolled patients aged 18 to 75 years with active RA who had failed conventional synthetic disease-modifying antirheumatic drugs (DMARDs) and were naïve to biologic and/or targeted synthetic DMARDs. All patients received an auricular vagus nerve stimulator and were randomized 1:1 to active stimulation or sham. The primary endpoint was the proportion of patients achieving 20% improvement in American College of Rheumatology criteria (ACR20) at week 12. Secondary endpoints included mean changes in disease activity score of 28 joints with C-reactive protein (DAS28-CRP) and Health Assessment Questionnaire-Disability Index (HAQ-DI).A total of 113 patients (mean age 54 years; 82% female) enrolled, and 101 patients (89.4%) completed week 12. ACR20 response at week 12 was 25.0% for active stimulation versus 26.9% for sham (difference vs. sham, -1.9; 95% CI, -18.8, 14.9, P = 0.823). The least square mean ± SE change in DAS28-CRP was -0.95 ± 0.16 for active stimulation and -0.66 ± 0.16 for sham (P = 0.201); in HAQ-DI it was -0.19 ± 0.06 for active stimulation and -0.02 ± 0.06 for sham (P = 0.044). Adverse events occurred in 17 patients (15%); all were mild or moderate.Auricular VNS did not meaningfully improve RA disease activity. If VNS with other modalities is pursued in the future for the treatment of RA, larger, controlled studies will be needed to understand its utility.
Assessing the Ability of Long Noncoding RNA Expression to Predict Patient Outcomes in Pediatric AML
Authors: Zachary R. McCaw, Paul G. Richardson, Lee-Jen Wei
Journal: Journal of Clinical Oncology (2023)

Farrar et al 1 conducted an important and comprehensive study to explore whether a 37-gene long noncoding RNA signature (IncScore) would improve prediction of overall survival (OS) and event-free survival (EFS) in pediatric AML (pAML).They concluded that the lncScore independently predicted patient outcomes, enhancing the power of traditional cytogenetic and mutational stratifiers.Moreover, they suggest that lncScore may be used as a single predictor, replacing the complex traditional stratification procedure for pAML.
Synovial Tissue Heterogeneity in Japanese Patients With Rheumatoid Arthritis Elucidated Using a <scp>Cell‐Type</scp> Deconvolution Approach
Authors: Sotaro Nakajima, Haruka Tsuchiya, Mineto Ota, Megumi Ogawa, Saeko Yamada, Ryochi Yoshida, Junko Maeda, Harumi Shirai, Taro Kasai, Jun Hirose, Keita Ninagawa, Yuichiro Fujieda, Takeshi Iwasaki, Yoshimi Aizaki, Hiroshi Kajiyama, Masakazu Matsushita, Eiryo Kawakami, Naoto Tamura, Toshihide Mimura, Koichiro Ohmura, Akio Morinobu, Tatsuya Atsumi, Yoshiya Tanaka, Tsutomu Takeuchi, Sakae Tanaka, Tomohisa Okamura, Keishi Fujio
Journal: Arthritis & Rheumatology (2023)

Recent advances in single-cell RNA sequencing technology have improved our understanding of the immunological landscape of rheumatoid arthritis (RA). We aimed to stratify the synovium from East Asian patients with RA by immune cell compositions and gain insight into the inflammatory drivers of each synovial phenotype.Synovial tissues were obtained from East Asian patients in Japan with RA (n = 41) undergoing articular surgery. The cellular composition was quantified by a deconvolution approach using a public single-cell-based reference. Inflammatory pathway activity was calculated by gene set variation analysis, and chromatin accessibility was evaluated using assay of transposase accessible chromatin-sequencing.We stratified RA synovium into three distinct subtypes based on the hierarchical clustering of cellular composition data. One subtype was characterized by abundant HLA-DRAhigh synovial fibroblasts, autoimmune-associated B cells, GZMK+ GZMB+ CD8+ T cells, interleukin (IL)1-β+ monocytes, and plasmablasts. In addition, tumor necrosis factor (TNF)-α, interferons (IFNs), and IL-6 signaling were highly activated in this subtype, and the expression of various chemokines was significantly enhanced. Moreover, we found an open chromatin region overlapping with RA risk locus rs9405192 near the IRF4 gene, suggesting the genetic background influences the development of this inflammatory synovial state. The other two subtypes were characterized by increased IFNs and IL-6 signaling, and expression of molecules associated with degeneration, respectively.This study adds insights into the synovial heterogeneity in East Asian patients and shows a promising link with predominant inflammatory signals. Evaluating the site of inflammation has the potential to lead to appropriate drug selection that matches the individual pathology.
Metabolomics and Machine Learning Identify Metabolic Differences and Potential Biomarkers for Frequent Versus Infrequent Gout Flares
Authors: Ming Wang, Rui Li, Han Qi, Lei Pang, Lingling Cui, Zhen Liu, Jie Lu, Rong Wang, Shuhui Hu, Ningning Liang, Yongzhen Tao, Nicola Dalbeth, Tony R. Merriman, Robert Terkeltaub, Huiyong Yin, Changgui Li
Journal: Arthritis & Rheumatology (2023)

The objective of this study was to discover differential metabolites and pathways underlying infrequent gout flares (InGF) and frequent gout flares (FrGF) using metabolomics and to establish a predictive model by machine learning (ML) algorithms.Serum samples from a discovery cohort of 163 patients with InGF and 239 patients with FrGF were analyzed by mass spectrometry-based untargeted metabolomics to profile differential metabolites and explore dysregulated metabolic pathways using pathway enrichment analysis and network propagation-based algorithms. ML algorithms were performed to establish a predictive model based on selected metabolites, which was further optimized by a quantitative targeted metabolomics method and validated in an independent validation cohort with 97 participants with InGF and 139 participants with FrGF.A total of 439 differential metabolites between InGF and FrGF groups were identified. Top dysregulated pathways included carbohydrates, amino acids, bile acids, and nucleotide metabolism. Subnetworks with maximum disturbances in the global metabolic networks featured cross-talk between purine metabolism and caffeine metabolism, as well as interactions among pathways involving primary bile acid biosynthesis, taurine and hypotaurine metabolism, alanine, aspartate, and glutamate metabolism, suggesting epigenetic modifications and gut microbiome in metabolic alterations underlying InGF and FrGF. Potential metabolite biomarkers were identified using ML-based multivariable selection and further validated by targeted metabolomics. Area under receiver operating characteristics curve for differentiating InGF and FrGF achieved 0.88 and 0.67 for the discovery and validation cohorts, respectively.Systematic metabolic alterations underlie InGF and FrGF, and distinct profiles are associated with differences in gout flare frequencies. Predictive modeling based on selected metabolites from metabolomics can differentiate InGF and FrGF.
Role of Extracellular Vesicles in the Propagation of Lung Fibrosis in Systemic Sclerosis
Authors: Joe E. Mouawad, Matthew Sanderson, Shailza Sharma, Kristi L. Helke, Joseph M. Pilewski, Satish N. Nadig, Carol Feghali‐Bostwick
Journal: Arthritis & Rheumatology (2023)

Systemic sclerosis (SSc) has the highest mortality rate among the rheumatic diseases, with lung fibrosis leading as the cause of death. A characteristic of severe SSc-related lung fibrosis is its progressive nature. Although most research has focused on the pathology of the fibrosis, the mechanism mediating the fibrotic spread remains unclear. We hypothesized that extracellular vesicle (EV) communication drives the propagation of SSc lung fibrosis.
Single-cell profiling reveals age-associated immunity in atherosclerosis
Authors: Virginia Smit, Jill de Mol, Frank H Schaftenaar, Marie A C Depuydt, Rimke J Postel, Diede Smeets, Fenne W M Verheijen, Laurens Bogers, Janine van Duijn, Robin A F Verwilligen, Hendrika W Grievink, Mireia N A Bernabé Kleijn, Eva van Ingen, Maaike J M de Jong, Lauren Goncalves, Judith A H M Peeters, Harm J Smeets, Anouk Wezel, Julia K Polansky, Menno P J de Winther, Christoph J Binder, Dimitrios Tsiantoulas, Ilze Bot, Johan Kuiper, Amanda C Foks
Journal: Cardiovascular Research (2023)

Aging is a dominant driver of atherosclerosis and induces a series of immunological alterations, called immunosenescence. Given the demographic shift towards elderly, elucidating the unknown impact of aging on the immunological landscape in atherosclerosis is highly relevant. While the young Western diet-fed Ldlr-deficient (Ldlr-/-) mouse is a widely used model to study atherosclerosis, it does not reflect the gradual plaque progression in the context of an aging immune system as occurs in humans.
Associations of COVID-19 symptoms with omicron subvariants BA.2 and BA.5, host status, and clinical outcomes in Japan: a registry-based observational study
Authors: Sho Nakakubo, Naoki Kishida, Kenichi Okuda, Keisuke Kamada, Masami Iwama, Masaru Suzuki, Isao Yokota, Yoichi M Ito, Yasuyuki Nasuhara, Richard C Boucher, Satoshi Konno
Journal: The Lancet Infectious Diseases (2023)
Effect of bariatric surgery on cardio-psycho-metabolic outcomes in severe obesity: A randomized controlled trial
Authors: Ann-Cathrin Koschker, Bodo Warrings, Caroline Morbach, Florian Seyfried, Pius Jung, Ulrich Dischinger, Frank Edelmann, Martin J. Herrmann, Christine Stier, Stefan Frantz, Uwe Malzahn, Stefan Störk, Martin Fassnacht
Journal: Metabolism (2023)

Randomized evidence comparing the cardiovascular effects of surgical and conservative weight management is lacking.In this single-center, open-label randomized trial, obese patients with indication for Roux-en-Y gastric bypass (RYGB) and able to perform treadmill cardiopulmonary exercise testing (CPET) were included. After a 6-12 month run-in phase of multimodal anti-obesity treatment, patients were randomized to RYGB or psychotherapy-enhanced lifestyle intervention (PELI) and co-primary endpoints were assessed 12 months later. Thereafter, PELI patients could opt for surgery and patients were reassessed 24 months after randomization. Co-primary endpoints were mean change (95 % confidence intervals) in peak VO2 (ml/min/kg body weight) in CPET and the physical functioning scale (PFS) of the Short Form health survey (SF-36).Of 93 patients entering the study, 60 were randomized. Among these (median age 38 years; 88 % women; mean BMI 48·2 kg/m2), 46 (RYGB: 22 and PELI: 24) were evaluated after 12 months. Total weight loss was 34·3 % after RYGB vs. 1·2 % with PELI, while peak VO2 increased by +4·3 ml/min/kg (2·7, 5·9) vs +1·1 ml/min/kg (-0·2, 2·3); p < 0·0001. Respective improvement in PFS score was +40 (30, 49) vs +10 (1, 15); p < 0·0001. 6-minute walking distance also favored the RYGB group: +44 m (17, 72) vs +6 m (-14, 26); p < 0·0001. Left ventricular mass decreased after RYGB, but not with PELI: -32 g (-46, -17) vs 0 g (-13,13); p < 0·0001. In the non-randomized follow-up, 34 patients were assessed. Favorable changes were sustained in the RYGB group and were repeated in the 15 evaluated patients that opted for surgery after PELI.Among adults with severe obesity, RYGB in comparison to PELI resulted in improved cardiopulmonary capacity and quality of life. The observed effect sizes suggest that these changes are clinically relevant.
HLA-E–restricted SARS-CoV-2–specific T cells from convalescent COVID-19 patients suppress virus replication despite HLA class Ia down-regulation
Authors: Hongbing Yang, Hong Sun, Simon Brackenridge, Xiaodong Zhuang, Peter A C Wing, Max Quastel, Lucy Walters, Lee Garner, Beibei Wang, Xuan Yao, Suet Ling Felce, Yanchun Peng, Shona Moore, Bas W.A. Peeters, Margarida Rei, Joao Canto Gomes, Ana Tomas, Andrew Davidson, Malcolm G. Semple, Lance C.W. Turtle, Peter J.M. Openshaw, J. Kenneth Baillie, Alexander J. Mentzer, Paul Klenerman, Persephone Borrow, Tao Dong, Jane A McKeating, Geraldine M Gillespie, Andrew J McMichael
Journal: Science Immunology (2023)

Pathogen-specific CD8 + T cell responses restricted by the nonpolymorphic nonclassical class Ib molecule human leukocyte antigen E (HLA-E) are rarely reported in viral infections. The natural HLA-E ligand is a signal peptide derived from classical class Ia HLA molecules that interact with the NKG2/CD94 receptors to regulate natural killer cell functions, but pathogen-derived peptides can also be presented by HLA-E. Here, we describe five peptides from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that elicited HLA-E–restricted CD8 + T cell responses in convalescent patients with coronavirus disease 2019. These T cell responses were identified in the blood at frequencies similar to those reported for classical HLA-Ia–restricted anti–SARS-CoV-2 CD8 + T cells. HLA-E peptide–specific CD8 + T cell clones, which expressed diverse T cell receptors, suppressed SARS-CoV-2 replication in Calu-3 human lung epithelial cells. SARS-CoV-2 infection markedly down-regulated classical HLA class I expression in Calu-3 cells and primary reconstituted human airway epithelial cells, whereas HLA-E expression was not affected, enabling T cell recognition. Thus, HLA-E–restricted T cells could contribute to the control of SARS-CoV-2 infection alongside classical T cells.
Risk of male breast cancer after Hodgkin lymphoma
Authors: Simone de Vries, Inge M. Krul, Michael Schaapveld, Cecile P. M. Janus, Saskia E. Rademakers, Judith M. Roesink, Marten R. Nijziel, Yavuz M. Bilgin, Berthe M. P. Aleman, Flora E. van Leeuwen
Journal: Blood (2023)
Polymorphic KIR3DL3 expression modulates tissue-resident and innate-like T cells
Authors: William H. Palmer, Laura Ann Leaton, Ana Campos Codo, Bergren Crute, James Roest, Shiying Zhu, Jan Petersen, Richard P. Tobin, Patrick S. Hume, Matthew Stone, Adrie van Bokhoven, Mark E. Gerich, Martin D. McCarter, Yuwen Zhu, William J. Janssen, Julian P. Vivian, John Trowsdale, Andrew Getahun, Jamie Rossjohn, John Cambier, Liyen Loh, Paul J. Norman
Journal: Science Immunology (2023)

Most human killer cell immunoglobulin-like receptors (KIR) are expressed by natural killer (NK) cells and recognize HLA class I molecules as ligands. KIR3DL3 is a conserved but polymorphic inhibitory KIR recognizing a B7 family ligand, HHLA2, and is implicated for immune checkpoint targeting. The expression profile and biological function of KIR3DL3 have been somewhat elusive, so we searched extensively for KIR3DL3 transcripts, revealing highly enriched expression in γδ and CD8
Revealing and harnessing CD39 for the treatment of colorectal cancer and liver metastases by engineered T cells
Authors: Alessia Potenza, Chiara Balestrieri, Martina Spiga, Luca Albarello, Federica Pedica, Francesco Manfredi, Beatrice Claudia Cianciotti, Claudia De Lalla, Oronza A Botrugno, Cristina Faccani, Lorena Stasi, Elena Tassi, Silvia Bonfiglio, Giulia Maria Scotti, Miriam Redegalli, Donatella Biancolini, Barbara Camisa, Elena Tiziano, Camilla Sirini, Monica Casucci, Chiara Iozzi, Danilo Abbati, Fabio Simeoni, Dejan Lazarevic, Ugo Elmore, Guido Fiorentini, Giulia Di Lullo, Giulia Casorati, Claudio Doglioni, Giovanni Tonon, Paolo Dellabona, Riccardo Rosati, Luca Aldrighetti, Eliana Ruggiero, Chiara Bonini
Journal: Gut (2023)

Colorectal tumours are often densely infiltrated by immune cells that have a role in surveillance and modulation of tumour progression but are burdened by immunosuppressive signals, which might vary from primary to metastatic stages. Here, we deployed a multidimensional approach to unravel the T-cell functional landscape in primary colorectal cancers (CRC) and liver metastases, and genome editing tools to develop CRC-specific engineered T cells.We paired high-dimensional flow cytometry, RNA sequencing and immunohistochemistry to describe the functional phenotype of T cells from healthy and neoplastic tissue of patients with primary and metastatic CRC and we applied lentiviral vectors (LV) and CRISPR/Cas9 genome editing technologies to develop CRC-specific cellular products.We found that T cells are mainly localised at the front edge and that tumor-infiltrating T cells co-express multiple inhibitory receptors, which largely differ from primary to metastatic sites. Our data highlighted CD39 as the major driver of exhaustion in both primary and metastatic colorectal tumours. We thus simultaneously redirected T-cell specificity employing a novel T-cell receptor targeting HER-2 and disrupted the endogenous TCR genes (TCR editing (TCRED)) and the CD39 encoding gene (ENTPD1), thus generating TCREDENTPD1KOHER-2-redirected lymphocytes. We showed that the absence of CD39 confers to HER-2-specific T cells a functional advantage in eliminating HER-2+ patient-derived organoids in vitro and in vivo.HER-2-specific CD39 disrupted engineered T cells are promising advanced medicinal products for primary and metastatic CRC.
Inserting EF1α-driven CD7-specific CAR at CD7 locus reduces fratricide and enhances tumor rejection
Authors: Jie Jiang, Jiangqing Chen, Chan Liao, Yanting Duan, Yajie Wang, Kai Shang, Yanjie Huang, Yongming Tang, Xiaofei Gao, Ying Gu, Jie Sun
Journal: Leukemia (2023)
RUNX1 mutations mitigate quiescence to promote transformation of hematopoietic progenitors in Fanconi anemia
Authors: William Marion, Tiago Koppe, Chun-Chin Chen, Dahai Wang, Katie Frenis, Sara Fierstein, Prerana Sensharma, Olivia Aumais, Michael Peters, Sonya Ruiz-Torres, Tafadzwa Chihanga, Steffen Boettcher, Akiko Shimamura, Daniel E. Bauer, Thorsten Schlaeger, Susanne I. Wells, Benjamin L. Ebert, Daniel Starczynowski, Edroaldo Lummertz da Rocha, R. Grant Rowe
Journal: Leukemia (2023)
The international Unity study for antivirals against mpox is a blueprint for future epidemics
Authors: Erica Telford, Beatriz Grinsztejn, Inge Christoffer Olsen, Nicolas Pulik, France Mentré, Skerdi Haviari, Maxime Hentzien, Olivier Ségéral, Miquel B. Ekkelenkamp, Dimie Ogoina, Nathalie Strub-Wourgaft, Alpha Diallo, Yazdan Yazdanpanah, Alexandra Calmy
Journal: Nature Medicine (2023)
Single-cell protein expression profiling resolves circulating and resident memory T cell diversity across tissues and infection contexts
Authors: Maximilien Evrard, Etienne Becht, Raissa Fonseca, Andreas Obers, Simone L. Park, Nagela Ghabdan-Zanluqui, Jan Schroeder, Susan N. Christo, Dominik Schienstock, Junyun Lai, Thomas N. Burn, Allison Clatch, Imran G. House, Paul Beavis, Axel Kallies, Florent Ginhoux, Scott N. Mueller, Raphael Gottardo, Evan W. Newell, Laura K. Mackay
Journal: Immunity (2023)
When a calorie is not just a calorie: Diet quality and timing as mediators of metabolism and healthy aging
Authors: Maria M. Mihaylova, Amandine Chaix, Mirela Delibegovic, Jon J. Ramsey, Joseph Bass, Girish Melkani, Rajat Singh, Zheng Chen, William W. Ja, Michele Shirasu-Hiza, Mary N. Latimer, Julie A. Mattison, Anna E. Thalacker-Mercer, Vishwa Deep Dixit, Satchidananda Panda, Dudley W. Lamming
Journal: Cell Metabolism (2023)
CXCR3 expression in regulatory T cells drives interactions with type I dendritic cells in tumors to restrict CD8+ T cell antitumor immunity
Authors: Mariela A. Moreno Ayala, Timothy F. Campbell, Chenyu Zhang, Noa Dahan, Alissa Bockman, Varsha Prakash, Lawrence Feng, Theo Sher, Michel DuPage
Journal: Immunity (2023)
Hypertensive disorders of pregnancy
Authors: Pensée Wu, Marcus Green, Jenny E Myers
Journal: BMJ (2023)

ABSTRACT Hypertensive disorders of pregnancy (HDP) are one of the most commonly occurring complications of pregnancy and include chronic hypertension, gestational hypertension, and pre-eclampsia. New developments in early pregnancy screening to identify women at high risk for pre-eclampsia combined with targeted aspirin prophylaxis could greatly reduce the number of affected pregnancies. Furthermore, recent advances in the diagnosis of pre-eclampsia, such as placental growth factor based testing, have been shown to improve the identification of those pregnancies at highest risk of severe complications. Evidence from trials has refined the target blood pressure and timing of delivery to manage chronic hypertension and pre-eclampsia with non-severe features, respectively. Importantly, a wealth of epidemiological data now links HDP to future cardiovascular disease and diabetes decades after an affected pregnancy. This review discusses the current guidelines and research data on the prevention, diagnosis, management, and postnatal follow-up of HDP. It also discusses the gap in knowledge regarding the long term risks for cardiovascular disease following HDP and illustrates the importance of improving adherence to postnatal guidelines to monitor hypertension and the need for more research focused on primary prevention of future cardiovascular disease in women identified as being at high risk because of HDP.
Correction: An MDM2 degrader for treatment of acute leukemias
Authors: Bridget K. Marcellino, Xiaobao Yang, H. Ümit Kaniskan, Claudia Brady, He Chen, Karie Chen, Xing Qiu, Cara Clementelli, Lauren Herschbein, Zhijun Li, Sebastian Elghaity-Beckley, Joann Arandela, Brianna Kelly, Ronald Hoffman, Jing Liu, Yue Xiong, Jian Jin, Alan H. Shih
Journal: Leukemia (2023)